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Purpose Depression is associated with recurrent cardiac events and death in patients with coronary heart disease and congestive heart failure. Furthermore, depression may be associated with reduced completion of outpatient cardiac rehabilitation (CR), an empirically supported treatment for patients with coronary heart disease and congestive heart failure that reduces recurrent coronary events and cardiac mortality. The goal of the current systematic review and meta-analysis was to explore the association between depression and outpatient CR completion. Method A systematic literature review cross-referenced 3 electronic databases (PsycINFO, MEDLINE, and Dissertation Abstracts International) from inception through February 15, 2015. Studies quantifying an association between depression and outpatient CR completion were identified for review. A random-effects model was used to pool quantitative data, moderators were tested, and publication bias was analyzed. Results Seventeen studies with 19 independent samples consisting of 30 586 cardiac patients were included in the meta-analysis. A moderate inverse relationship between depression and outpatient CR completion was observed (g = -0.44; 95% CI, -0.59 to -0.29), indicating that depressed CR patients were significantly less likely to complete their prescribed CR programs. No significant moderator variables were identified. A minor amount of publication bias was detected. Conclusion Depression is associated with reduced outpatient CR completion rates. Future research should focus on attendance interventions for depressed CR patients, as completion of outpatient CR reduces cardiac and all-cause mortality.

Objective To explore differences in blood cytokine profiles among distinct bronchopulmonary dysplasia (BPD) patterns. Study design We evaluated blood spots collected from 943 infants born at ≤1000 g and surviving to 28 days on postnatal days 1, 3, 7, 14, and 21 for 25 cytokines. Infants were assigned to the following lung disease patterns: (1) no lung disease (NLD); (2) respiratory distress syndrome without BPD; (3) classic BPD (persistent exposure to supplemental oxygen until 28 days of age); or (4) atypical BPD (period without supplemental oxygen before 28 days). Median cytokine levels for infants with BPD were compared with the IQR of results among infants with NLD. Results The distribution of enrolled infants by group was as follows: 69 (NLD), 73 (respiratory distress syndrome), 381 (classic BPD), and 160 (atypical BPD). The remaining 260 infants could not be classified because of missing data (104) or not fitting a predefined pattern (156). Median levels of 3 cytokines (elevated interleukin [IL]-8, matrix metalloproteinase-9; decreased granulocyte macrophage colony-stimulating factor) fell outside the IQR for at least 2 time points in both infants with atypical and classic BPD. Profiles of 7 cytokines (IL-6, IL-10, IL-18, macrophage inflammatory protein-1α, C-reactive protein, brain-derived neurotrophic factor, regulated on activation, normal T cell expressed and secreted) differed between infants with classic and atypical BPD. Conclusions Blood cytokine profiles may differ between infants developing classic and atypical BPD. These dissimilarities suggest the possibility that differing mechanisms could explain the varied patterns of pathophysiology of lung disease in extremely premature infants.

Introduction: Environmental tobacco smoke (ETS) is the third leading preventable cause of death in the United States. Few biopsychosocial studies have addressed knowledge of specific ETS health effects, attitudes toward ETS, and personal preventive efforts related to ETS. Method: We surveyed a diverse U.S. community sample of convenience (N = 328) in Flagstaff, Arizona, to examine the following: (a) Does ETS knowledge measured using two response formats, open-ended (OPEF) versus closed-ended (CLEF), result in differences in apparent knowledge? and (b) what are demographic predictors of ETS knowledge, attitudes, and preventive behaviors? Results: Participants scored significantly higher on the ETS knowledge CLEF than OPEF. In regression analyses, predictors of ETS knowledge on the OPEF scale included ethnicity, age, and smoking status; the model predicting knowledge using the CLEF scale was not significant. Knowledge and smoking status, as measured on both the CLEF and the OPEF, were significant predictors of negative attitudes. Additional predictors of attitudes included income for the model using the OPEF and gender for the model using the CLEF. Predictors of preventive behaviors included attitudes and age (OPEF and CLEF models). Discussion: Differences in apparent ETS knowledge of specific ETS health effects by varying response format suggest that open-ended surveys may be useful in identifying specific content areas to address in public health education efforts. Various demographic variables predicted ETS knowledge, attitudes, and preventive behaviors, highlighting specific populations to target in public health interventions relating to ETS, such as non-White and younger populations.

Background. Physical activity, in particular vigorous activity (i.e., ≥6 METs), lowers mortality from chronic diseases such as cardiovascular disease (CVD). The 7-Day Physical Activity Recall (PAR), a self-administered activity log (LOG), and heart rate monitoring (HR) were used to quantify activity patterns among sedentary adults. We hypothesized that individuals in this population could accurately estimate the duration, but not the intensity, of their activity. Methods. Sedentary adults (n = 94, 47.8 ± 7.1 years) completed two PARs 1 week apart and underwent HR monitoring while completing a LOG for 1 day during the PAR assessment interval. Results. The relationship between PARs (kcal · kg−1 · day−1 ) was significant (r = 0.80, 95% CI 0.68–0.87) among individuals (n = 63) reporting “typical” activity patterns and among all individuals (n = 94) reporting “typical” and “not typical” activity patterns combined (r = 0.44, 95% CI 0.26–0.59). Quantity of moderate activity was greater (P = 0.0001) on PAR and LOG compared to that measured by HR. Quantity of hard (vigorous) activity was also greater (P = 0.019) on LOG compared to that measured by HR. Conclusions. Sedentary adults tend to overestimate the intensity of their activity, specifically for moderate activity. Furthermore, the aerobic capacity of our sedentary adult sample (about 7.3 METs) suggests that the definition of a threshold intensity level of activity necessary to reduce mortality from CVD should be reexamined, because a value of ≥6 METs appears to be too high in this population.

Type D personality is associated with recurrent coronary heart disease (CHD) risk but there is limited and inconsistent evidence regarding incident risk among persons free of clinical CHD. We examined the association between Type D personality and coronary heart disease (CHD) risk in apparently healthy adults. We also explored the association of these traits with waist circumference, body mass index (BMI), and inhibited physician consultation behavior. Cross-sectional study of North American retirement-aged residents (N = 303). The primary outcome variable was a modified 10-year absolute CHD risk score from the Framingham Heart Study. Secondary outcomes included adiposity and a 5-item measure of patient/provider interaction inhibition. We regressed CHD risk on negative affect (NA), social inhibition (SI), and the NAxSI interaction (i.e., the Type D personality) and repeated these analyses for adiposity and for patient/provider interaction inhibition. We also contrasted CHD risk across Type D and non-Type D categories. None of the personality variables were associated with CHD risk for the whole sample (regression coefficients from −0.11 to .10, Ps > 0.29) or in gender-specific analyses. For adiposity, NA was positively associated and SI was negatively associated with BMI in women (Ps

Phenobarbital, when administered prenatally to animals, produced profound and prominent effects on reproduction. Preliminary analysis of a unique cohort of adolescents who were exposed to phenobarbital in utero suggests that long-term effects may be evident in the human as well.

Regular physical activity produces beneficial effects on health, but the exercise prescription needed to improve cardiovascular disease risk factors in free-living sedentary individuals remains unclear.Sedentary adults (N = 492, 64.0% women) were randomized to 1 of 4 exercise-counseling conditions or to a physician advice comparison group. The duration (30 minutes) and type (walking) of exercise were held constant, while exercise intensity and frequency were manipulated to form 4 exercise prescriptions: moderate intensity-low frequency, moderate intensity-high frequency (HiF), hard intensity (HardI)-low frequency, and HardI-HiF. Comparison group participants received physician advice and written materials regarding recommended levels of exercise for health. Outcomes included 6- and 24-month changes in cardiorespiratory fitness (maximum oxygen consumption), high-density lipoprotein cholesterol (HDL-C) level, and the total cholesterol-HDL-C ratio.At 6 months, the HardI-HiF, HardI-low-frequency, and moderate-intensity-HiF conditions demonstrated significant increases in maximum oxygen consumption (P.01 for all), but only the HardI-HiF condition showed significant improvements in HDL-C level (P.03), total cholesterol-HDL-C ratio (P.04), and maximum oxygen consumption (P.01) compared with physician advice. At 24 months, the increases in maximum oxygen consumption remained significantly higher than baseline in the HardI-HiF, HardI-low-frequency, and moderate-intensity-HiF conditions and in the HardI-HiF group compared with physician advice (P.01 for all), but no significant effects on HDL-C level (P = .57) or total cholesterol-HDL-C ratio (P = .64) were observed.Exercise counseling with a prescription for walking at either a HardI or a HiF produced significant long-term improvements in cardiorespiratory fitness. More exercise or the combination of HardI plus HiF exercise may provide additional benefits, including larger fitness changes and improved lipid profiles.

Background: Anxiety symptoms are associated with elevated coronary heart disease (CHD) risk, but it is not known whether such associations extend to anxiety disorders or if they are independent of depression. We sought to determine if generalized anxiety disorder is associated with elevated CHD risk, and whether this association is independent of or interacts with major depressive disorder. Methods: Generalized anxiety and major depressive disorders were assessed in a cross-sectional survey of a representative sample of U.S. adults aged 25–74 (N=3032). Coronary heart disease risk was determined by self-reported smoking status, body mass index, and recent medication use for hypertension, hypercholesterolemia, and diabetes. Results: Generalized anxiety disorder independently predicted increased CHD risk (F(1,3018)=5.14; b=0.39; 95% confidence interval (0.05–0.72)) and tended to denote the greatest risk in the absence of major depressive disorder. Limitations: The cross-sectional design cannot determine the causal direction of the association. Conclusions: Generalized anxiety disorder appears to be associated with elevated CHD risk in the general population. It may denote excess CHD risk relative to major depressive disorder, and clinicians should consider CHD risk when treating generalized anxiety disorder. D 2005 Elsevier B.V. All rights reserved.

Sedentary adults (N = 379) were randomly assigned in a 2 x 2 design to walk 30 min per day at a frequency of either 3-4 or 5-7 days per week, at an intensity of either 45%-55% or 65%-75% of maximum heart rate reserve. Analyses of exercise accumulated over 6 months showed greater amounts completed in the higher frequency (p = .0001) and moderate intensity (p = .021) conditions. Analyses of percentage of prescribed exercise completed showed greater adherence in the moderate intensity(p = .02) condition. Prescribing a higher frequency increased the accumulation of exercise without a decline in adherence, whereas prescribing a higher intensity decreased adherence and resulted in the completion of less exercise.

A large number of studies in recent years have described protein and nitrogen metabolism in the neonate. However, the majority of these data are difficult to interpret because of a number of confounding variables, particularly in very low birth weight (VLBW) infants. In contrast, application of state-of-the-art tracer isotopic and molecular biology methods in isolated cell system and whole animals has resulted in major advances in our understanding of the regulation of protein breakdown, synthesis, and protein accretion. The following workshop summary reviews the recent developments in basic physiology of protein metabolism in cellular and animal models in relation to human preterm infants, and identifies the important areas toward which future basic and clinical research should be directed to provide for optimal nitrogen accretion and growth of the VLBW infant.

Over the past decade many exciting advances have been made with regard to the survival, medical care, and outcome of extremely low birth weight (ELBW) infants (those who weigh

(1995). Measuring the Experience, Expression, and Control of Anger. Issues in Comprehensive Pediatric Nursing: Vol. 18, No. 3, pp. 207-232.

The US Food and Drug Administration (FDA) has proposed new labelling regulations that describe alternative approaches for providing additional information to support labelling a drug, already approved for use in adults, for use in children. Therefore, the study of drugs in paediatric populations may now be encouraged. Paediatric pharmacokinetic studies are an important part of these trials. This action by the FDA may help resolve the ethical and technological concerns about the performance of clinical trials in children, and may render paediatric clinical trials more feasible. Most investigations in children are opportunistic in nature and their design is often constrained by a requisite noninvasive approach. Appropriately applied population-based techniques for both pharmacokinetic and pharmacodynamic data analysis may represent the most robust approach for generating a sufficiently large and accurate database for the use of new or old drugs in paediatric patients. Accordingly, this information, which is crucial for paediatric labelling of any drug product, must be obtained in infants and children if we are to truly individualise therapy for paediatric patients. The funding of 6 Pediatric Pharmacology Research Units by the US National Institutes of Health, and guidelines for application of pharmacokinetic methods to children may further contribute to the performance of paediatric clinical trials.

The compliance with treatment of acute otitis media in 300 pediatric outpatients was evaluated. Complete compliance in taking prescribed antibiotics was noted in 7.3% of the patients. Pharmacists dispensed less than prescribed amounts of antibiotics to 15% of patients. Bottles were incorrectly labeled 3% of the time. Volumes of 130 "teaspoons" examined varied from 2 to 9 ml. Parental understanding of the illness and of the effects of medication was inadequate and erroneous in many instances. Parents gave fewer than the prescribed number of doses in 36% of cases, and therapy was discontinued early in 37%. Recommendations for improving the quality of therapy for ambulatory pediatric patients are outlined.

The distribution of digoxin in the myocardium, skeletal muscle, erythrocytes, and plasma (or serum) was studied in 19 infants. There was a linear relationship between myocardium and serum concentrations and no saturation was observed over the serum concentration range of 0.5-8.6 ng/ml. Myocardium uptake of digoxin was nearly twice as great in infants as in adults at any given serum concentration. Erythrocyte: plasma concentration ratios of digoxin were one-third smaller during digitalization than during maintenance digoxin therapy. The latter ratios were also three times greater in infants than found previously in adults. Their findings are consistent with a greater apparent volume of distribution of digoxin in infants and may partly explain the unusually large therapeutic doses needed in infants.

Epidemiologic studies have provided much of the knowledge concerning adverse side effects of exposure to drugs and other xenobiotics transmitted via breast milk. Adverse effects can be immediate and usually recognizable or long-term and difficult to define. Acute effects may be due to individual idiosyncrasy, allergic reaction, or manifestation of acute toxicity. We need further human clinical investigations to determine actual dosing to nursing infants and to ascertain the existence of subtle and presently unrecognized long-term effects.

The elimination pharmacokinetics of tobramycin sulfate was studied in 25 newborn infants of birth weight 0.7 to 4.7 kg during 31 treatment episodes. The peak serum concentrations after a 2.5 mg/kg dose were usually within the therapeutic range of 5 to 10 micrograms/ml; however, the serum predose trough values were elevated above the theoretical safe limit of 2 micrograms/ml. Because of the prolonged serum elimination half-lives, a calculated extended dosage interval, sometimes greater than 24 hours, was necessary to obtain a predose trough of less than or equal to 2 micrograms/ml. The serum elimination half-lives inversely correlated with gestational age, extrauterine age, birth weight, and creatinine clearance. The very low ratio of tobramycin renal clearance to creatinine renal clearance was virtually constant and indicated a probable tubular reabsorption of tobramycin. A general dosage schedule based on birth weight was derived from the data. An alternative formula was derived to enable prediction of the tobramycin elimination half-life based on a combination of birth weight, gestational age, and extrauterine age for an infant younger than 7 days of age.

Neutron activation analysis was employed to quantitate the levels of mercury (Hg) in human tissue and body fluids. Statistical analysis revealed: 1. a. No significant differences (P > .05) in Hg levels among the members of each of the following groupings: (i) adult (15–91 years) and sub-adult (neonate through 14 years) frontal and cerebellar cortex, medulla, pons, midbrain, and adult thalamus. (ii) sub-adult thalamus, adult and sub-adult callosal white matter and angular and supramarginal gyri. (iii) the RBCs, plasma and urine obtained from apparently healthy volunteers. Also, there was no correlation among the Hg levels of the RBCs, plasma and urine of any single individual. 2. b. A significantly higher (P 3. c. A significantly higher (P 4. d. A significantly higher Hg level in the adult gastrocnemius muscle and corpus striatum compared to the tissue/body fluids listed in a.ii (P 5. e. A significant positive effect of age on thalamic Hg levels (adult > sub-adult: P

The labeled dosage schedule that has long been on pediatric aspirin preparations is at variance with the recommendation in authoritative medical references, studies demonstrating antipyretic effectiveness in children, and the prescribing habits of pediatricians as revealed by a poll conducted by the authors. Aspirin pharmacokinetics are influenced by a number of physiologic factors, as well as by dosage, and complicate the problem of assuring safe and effective pediatric use. Basic pharmacokinetic considerations indicate that the increase in size of individual doses needed to assure therapeutic salicyate blood levels, thereby removing the temptation of parents to administer the drug too often, is made permissible (i.e., safe while effective) by expanding the interdose interval to four hours instead of three. A revised pediatric aspirin disage schedule is presented that better meets the practices of the pediatric community and the needs of consumers.

A P P R O X I M A T E L Y 27 years ago, diethylstilbestrol came into widespread use in support of high-risk pregnancy. 316 Only 2 years ago, the relationship between adenocarcinoma of the vagina in young women and their exposure to stilbestrol while-still in utero came to light, 146 and in many ways even this discovery was "fortuitous." Adenocarcinoma of the vagina in adolescent females had been an extremely rare disease. If maternal stilbestrol therapy had been the cause of an increase in the incidence of some relatively more common and slightly less dramatic adolescent disease, say diabetes, it probably would still be undetected today. And so the age of long-range complications of fetal drug therapy has been ushered in. The implications of this are enormous. We are caught between therapeutic nihilism and the eternal truth of the drug l abe l "When this preparation is used in women of childbearing age, the potential benefits should be weighed against the possible hazards to the fetus." Where is there a scale so fine?.Not only are the benefits often unproved but the hazards, for the most part, are not known. It is the purpose of this monograph to condense a major portion of the literature concerning drugs administered during pregnancy as they pertain to the unintended pat ient the fetus. In so doing, it is hoped that the practicing physician will be made more aware of the effects that drugs have on fetal outcome and therefore will be better able to prevent unnecessary fetal exposure as well as being better

To improve agreement among observers, several investigators have recently proposed methods (algorithms) to standardize assessments of causality for presumed adverse drug reactions. We evaluated one such method in the context of an intensive pediatric drug surveillance program. Four observers rated 50 randomly selected case reports drawn from the program, first using only general guidelines and then, several months later, using the strict criteria of the algorithm. Agreement among observers was poor in both study phases. The presence of selected characteristics of adverse events (e.g., major severity) did not improve agreement in either phase of the study. We conclude that routine use of such algorithms in drug surveillance programs is not likely to be of benefit. Clinical Pharmacology and Therapeutics (1985) 38, 183–187; doi:10.1038/clpt.1985.156

IN the last twenty years, the staphylococcus has replaced the streptococcus as the chief cause of infection in maternity units. Sporadic and epidemic staphylococcal infection among newborn infants now ranks as one of the most serious hazards in the modern nursery (as summarized by Williams et al.1). Previous reports2 3 4 indicate that hexachlorophene-containing compounds applied to newborn infants reduce staphylococcal infections in nurseries and incidentally decrease nasal carriage of staphylococci. The opening of the new Palo Alto—Stanford Hospital Center in the summer of 1959 afforded an opportunity to institute a program centered around the prevention of staphylococcal colonization of the . . .

Biliverdin was detected in human amniotic fluid (9 to 16 weeks' gestation) by spectrophotometric analysis. Its presence was confirmed by a variety of techniques, including column chromatography, electrophoresis, ultraviolet fluorescence, thin-layer chromatography, and spectral analysis of the isolated compound. Detectable capacity of the placenta to reduce biliverdin was not present at any of the gestational ages studied. Capacity of fetal livers to catalyze NADH-dependent biliverdin reduction increased as gestation progressed toward term. Much higher specific activity was observed in liver obtained at autopsy from a 2-week-old child. On the basis of these results a unified theory regarding the presence of bile pigments in amniotic fluid is presented. The theory speculates that fetal hepatic biliverdin reductase may play a key role in the regulation of fetal hemoglobin metabolism during development and in the appearance of hemoglobin metabolites in amniotic fluid.

The essential biologically functional components of a model system for study of the reduction of p -nitrobenzoic acid (PNBA) to p -aminobenzoic acid (PABA) appeared to include: reduced nicotinamide adenine dinucleotide phosphate (NADPH) or reduced nicotinamide adenine dinucleotide (NADH) as initial electron donors, a flavin [flavin adenine dinucleotide (FAD), riboflavin-5-phosphate (FMN) or riboflavin], a sulfhydryl donor [e.g. reduced glutathione, (GSH) or cysteine] and a salt. The effects of the flavins and GSH were biphasic, showing activation in lower concentrations but inhibition in higher concentrations. The salt requirement appeared to be essential for the provision of optimal ionic strength. Variations of components of the model system increased the reaction rate to only about one-tenth that observed in the presence of boiled, dialyzed human placental or rat hepatic 104,000 g supernatant fractions. The reaction was inhibited (approximately 90 per cent) by carbon monoxide (CO) in incubation flasks containing boiled placental soluble fractions but was not inhibited by CO in model system reactions. Addition of 2.5 × 10 −3 M FMN to reaction vessels containing fresh, nondialyzed rat liver 104,000 g supernatant fractions markedly enhanced the reaction rate but addition of the same concentrations (inhibitory in model systems) to vessels containing dialyzed rat liver supernatant markedly inhibited the reaction. The results suggested differing mechanisms of electron transport from NADPH or NADH to PNBA for each of the various tissues studied as well as for homogenate subfractions of a given tissue.

Investigations of the capacity of human placental tissue to metabolize exogenous substrates revealed a system present in the soluble fraction of placental homogenates which increased the NADPH-dependent reduction of the azo-linkage of neoprontosil. Characterization of the enzyme system involved indicated striking differences in comparison to the azo-reductase system(s) present in hepatic tissues. Activity of the placental system was not affected by additions in vitro of magnesium ion, nicotinamide, NADP or NAD, and was only very slightly inhibited when incubated under atmospheres of pure oxygen of carbon monoxide. Placental azo-linkage reduction was enhanced by addition in vitro of EDTA, reduced glutathione and glucose 6-phosphate. The addition in vitro of flavins resulted in a decreased rate of conversion of neoprontosil to sulfanilamide. Flavin mononucleotide appeared to possess the greatest inhibitory effect. The system was also inhibited by sulfhydryl reagents. Comparisons of specific activities from homogenates of tissue obtained early in the gestational period vs. that obtained at term revealed no statistically significant differences. Studies on the mechanism of increased azo-linkage reduction revealed that an enzymicnonenzymic system involving d -glucose 6-phosphate: NADP oxidoreductase (EC 1.1.1.49) and 6-phospho- d -gluconate: NADP oxidoreductase (EC 1.1.1.44) could account for this increase in azo-linkage reduction.

Homogenates of human placental tissue obtained during therapeutic abortion at 9 to 12 weeks' gestation were investigated with regard to their capacity to metabolize a variety of drug substrates. Activities of NADPH and NADH-dependent reduction reactions were demonstrated employing several different nonendogenous compounds as substrates. Mechanisms for the reduction of aromatic nitro radicals and for the oxidative metabolisms of drugs, however, appeared to be lacking. Acetylation of p-aminobenzoic acid (PABA) was apparent in placental homogenates but acetylation of isoniazid could not be demonstrated. Catalysis of certain other conjugation reactions involving drug substrates also appeared to be deficient in early human placentas.

The plasma protein binding of diphenylhydantoin (DPH) in heparinized plasma from normal and hyperbilirubinemic newborn infants was investigated by means of an ultrafiltration technique utilizing 14 C-DPH. At room temperature, pH 7.4, and with a plasma concentration of 16 μg of DPH per milliliter, the unbound fraction of DPH in cord plasma from 13 normal infants was 10.6±1.4 (S.D.) per cent which is considerably higher than in adults. In a group of 20 hyperbilirubinemic newborn infants a positive correlation existed (r=0.55; p

Pharmacokinetics of gentamicin during peritoneal dialysis in children. The pharmacokinetics of gentamicin were examined on two occasions using intravenous and intraperitoneal routes in five children undergoing intermittent peritoneal dialysis for chronic renal failure. Serum, urine and dialysis fluid (DF) were assayed microbiologically for gentamicin and the data were subjected to computer analysis using equations evolved for a two-compartment model which considered the bi-directional flux of the drug. Following i.v. injection of 1 mg/kg of gentamicin, the apparent volume of distribution averaged 23% (range, 13 to 36%) of body wt (similar to normal), the mean half-life was 21hr (range, 9 to 37 hr; normal, 2 hr) and the peritoneal clearance averaged 4.0 ml/min/m 2 (range, 1.2 to 7.0 ml/min/m 2 ). During peritoneal administration of gentamicin (15 mg/liter of DF, 0.7 liters/m 2 administered in each cycle over 9 to 12 cycles), serum concentrations increased towards extrapolated steady-state levels which averaged 42% (range, 25 to 68%) of DF concentrations. The mean renal clearance of gentamicin was only 1.6 ml/min/m 2 while total body clearance ranged from 2.3 to 8.0 ml/min/m 2 , mostly occurring by a variable degree of dialysance. Peritoneal clearances and half-lives of gentamicin were similar in each patient following either treatment mode. The appreciable variability in gentamicin pharmacokinetics among adolescent patients with renal insufficiency necessitates dosage adjustments based on measurements of serum concentrations. Pharmacocinetique de la gentamycine au cours de la dialyse peritoneale chez l'enfant. La pharmacocinetique de la gentamycine a ete etudiee a deux reprises en utilisant les voies d'adminstration intra-veineuse et intraperitoneale chez 5 enfants soumis a des dialyses peritoneales periodiques pour insuffisance renale chronique. La gentamycine a ete dosee dans le serum, l'urine et le liquide de dialyse et les resultats ont ete traites en utilisant les equations d'un modele a deux compartiments qui prend en compte les flux bi-directionnels de la drogue. Apres l'injection i.v. de 1 mg/kg de gentamycine le volume apparent de distribution est en moyenne de 23% (13 a 36) du poids corporel, (valeur similaire a la normale), la demie vie moyenne de 21 heures (9 a 37) alores qu'elle est de 2 heures normalement et la clearance peritoneale est en moyenne de 4,0 ml/min/m 2 (1,2 a 7,0). Au cours de l'administration peritoneale de gentamycine (15 mg/l de liquide de dialyse, 0,7 l/m 2 a chaque cycle, 9 a 12 cycles) la concentration serique augmente vers un plateau, calcule par extrapolation, de 42% (25 a 68) de la concentration dans le liquide de dialyse. La clearance renale moyenne de la gentamycine etait de 1,6 ml/min/m 2 alors que la clearance totale allait de 2,3 a 8,0 ml/min/m 2 , surtout liee a un degre variable de dialysance. Les clearances peritoneales et les demies vies de la gentamycine etaient semblables chez le meme malade apres l'administration intra-veineuse ou intra-peritoneale. La variabilite importante de la pharmacocinetique de la gentamycine chez les malades adolescents atteints d'insuffisance renale necessite des ajustements de posologie fondes sur la determination des concentrations seriques.

(1978). Problems of Drug Administration in the Pediatric Patient. Drug Metabolism Reviews: Vol. 8, No. 2, pp. 303-318.

Compliance with therapeutic regimens has been found to be very low in pediatric ambulatory patients. Physicians must recognize the extent of noncompliance among their patients and become aware of the factors contributing to it. Several practical measures can be taken to enhance compliance and thus ensure better health care.

Most of the 5423 entrants in the Melbourne 1980 Big M Marathon were non-elite athletes. A study of a stratified random sample of 459 entrants (which represented a 42% response rate) found that, while entrants reflected the community standards of disease, they pursued healthier lifestyles. Preparation for the marathon led to a number of positive changes in the health standard of runners. The principal negative consequence of marathon training was the high rate of musculoskeletal problems (30%). Before the race, only 4% of participants had an adequate fluid intake; 33% had pre-existing problems, mainly involving muscles and joints (63%) and viral or gastrointestinal illnesses (41%). These entrants had a 60% less chance of finishing the race. Symptoms during the race were reported by 92% of entrants, but most of these were not serious; only 6% of entrants were unable to finish the race. The pattern of symptoms after the race was similar to that during the race; 50% of these resolved within three hours. Ninety-seven entrants (2%) required medical attention during the race. Serious problems were rare (only in three entrants), and no runner required admission to hospital for longer than 24 hours. Entrants were at greater risk of requiring medical attention or experiencing problems during and after the race if they had a shorter preparation (less than two months), ran fewer kilometres per week (less than 60 km/week) in the last two or three months before the race, and had performed fewer long training runs (more than 24 km).

The report on aspirin hepatitis by Zucker and colleagues in this issue of theJournal(page 1433) is the latest in a series of recent publications concerned with this phenomenon.1-5These reports follow at least two earlier communications on the same subject about 20 years ago.6,7Elevated activity of serum glutamic oxaloacetic and pyruvic transaminases (SGOT and SGPT) and other evidence of hepatotoxicity have been observed in patients receiving relatively high doses of aspirin or other salicylates such as choline salicylate or sodium salicylate. Most, but not all, of the reported cases involved children with rheumatic fever or rheumatoid arthritis rather than adults. One of the two patients reported by Zucker et al, as well as the three patients described by Seaman et al,5had systemic lupus erythematosus. Evidence of liver injury usually appeared at plasma salicylate concentrations above 25 mg/100 ml and disappeared promptly when salicylate

The disposition of methicillin in normal subjects and in subjects with cystic fibrosis (CF) was studied after administration of single intravenous doses of 15 mg/kg. The area under the serum concentration vs. time curve for CF patients was, on the average, only 75% of that found for normal subjects. The low concentrations in serum were caused by more rapid urinary excretion of the antibiotic, with rates of renal clearance averaging 425 ml/min per 1.73 m2 in the patients with CF and 362 ml/min per 1.73 m2 in the normal subjects. No differences were found in volumes of distribution and metabolic clearance rates of methicillin or in rates of creatinine clearance between the two groups of subjects. These data support previous findings with dicloxacillin which show that patients with CF exhibit unusually rapid, active tubular secretion of certain penicillins that may necessitate use of larger doses of these drugs in treatment of infections.

The disposition of theophylline was examined in seven children with asthma on two occasions before and on one occasion after chronic phenobarbital dosing (2 mg/kg/day). There was little intrapatient variability in apparent theophylline clearance between the two baseline assessments (0.081 versus 0.073 L/hr/kg). After 19 days of phenobarbital therapy, there was a significant increase in apparent theophylline clearance (0.104 versus 0.077 L/hr/kg), accompanied by a 30% decrease in the mean steady-state serum theophylline concentration (12.0 versus 8.4 micrograms/ml). The inducing effect of phenobarbital on theophylline metabolism may require theophylline dosage adjustment in patients with asthma who receive both drugs concurrently to maintain a given average steady-state theophylline concentration.

In its broadest sense, drug interaction may refer not only to the reaction between two or more therapeutic agents, but also to the interplay between an administered agent and a component of the host. Thus we may have drug-drug and drug-food interactions, and drug interactions with a particular clinical condition. The latter is particularly true in the rapidly growing infant or child, where host factors may result in qualitative as well as quantitative differences in drug interactions.

A metabolic case study of a four year old girl with renal tubular acidosis is presented. Renal function was normal except for inability to maintain a hydrogen gradient across the tubular epithelium. There was minimal limitation in total transfer of hydrogen ions into the urine, as expressed by titratable acidity, ammonia and reabsorbed bicarbonate. Histologic examination of a renal biopsy specimen disclosed dilatation of the tubules with some alteration in cellular surface. Enzyme assays for carbonic anhydrase and glutaminase activities were normal. Histochemical assay showed deficient staining for TPN diaphorase, but this was not corroborated by direct biochemical assay. No adequate explanation for the disorder was obtained, but it is suggested that a quantitative defect in energy production might have limited the renal secretion of free hydrogen ions.